Discovery of Dual‐Inhibitor Acyl Hydrazones for Acetylcholinesterase and Carbonic Anhydrase I/II: A Mechanistic Insight into Alzheimer's Disease

Abstract This study presents the synthesis of various non‐sulfonamide acyl hydrazone derivatives intended as multi‐target ligands for the treatment of Alzheimer's disease. The derivatives were thoroughly characterized using advanced spectroscopic techniques and their inhibitory activities against key enzymes, acetylcholinesterase (AChE) and human carbonic anhydrase I/II (hCA) were systematically assessed. The synthesized compounds demonstrated significant suppression of hCAs. The 4‐methoxycarbonyl compound ( 2a , Ki = 69.74 nM) exhibited a robust inhibitory effect against hCA I compared to the reference medication acetazolamide (AAZ, Ki = 373.46 nM). The 4‐dimethylamino compound ( 2b , K i of 120.36 nM) exhibited superior potency compared to AAZ (K i of 350.66 nM) against hCA II. 2,4‐dinitrobenzylidene ( 2n , K i of 69.18 nM) derivative displayed a remarkable inhibitory effect against AChE compared to tacrine (THA, K i of 205.78 nM). Additionally, in silico studies provided insight into the binding interactions enhancing the understanding of their multi‐target potential. This study identified compounds with varying affinities for hCA isoenzymes highlighting their potential as effective and selective hCA inhibitors. The reported compounds exhibited significant biological inhibitory potency indicating their potential as a promising lead compound against hCAs and AChE.